The association between body mass index, exercise capacity, and health-related quality of life in heart transplant recipients

Introduction Pre-transplant obesity and weight gain after heart transplantation are both associated with increased risk of poor clinical outcomes. We aimed to assess the association between overweight or obesity, exercise capacity, and health-related quality of life in heart transplant recipients. Methods This study is based on baseline data from the IronIC trial, in which we randomized 102 heart transplant recipients with iron deficiency to ferric derisomaltose or placebo. We performed cardio pulmonary exercise testing in all participants. To assess quality of life, we used the SF-36v2 questionnaire, using two sum scores: the physical component summary and the mental component summary. A minimal clinically important difference was defined as ≥2 and ≥3 for the physical and the mental component summary, respectively. Results 24/102 heart transplant recipients (24%) had a body mass index (BMI) ≥30 kg/m2. Peak oxygen consumption was 17.3 ± 4.6 ml/kg/min in the obese group vs. 24.7 ± 6.4 ml/kg/min in the group with a BMI <30 for a between-group difference of 7.4 (95% confidence interval 4.7–10.2) ml/kg/min: p < 0.001. The physical component summary score was on average 5.2 points lower in the patients with a body mass index ≥30 than in the lower weight group (p = 0.04). Conclusion Almost a quarter of our heart transplant recipients in long-term follow-up had a BMI ≥30 kg/m2. These patients had substantially lower exercise capacity and lower quality of life in the physical domain.


Introduction
Obesity prior to heart transplantation (HTx) and weight gain resulting in overweight or obesity after heart transplantation are associated with adverse cardiovascular events, allograft rejections and death (1)(2)(3)(4)(5)(6)(7)(8).The effect of obesity and overweight on physical capacity and quality of life after heart transplantation has not been well studied.
Compared with the general population, heart transplant recipients have reduced physical capacity and reduced healthrelated quality of life (9)(10)(11)(12).Exercise capacity improves substantially after heart transplantation (13).However, it stays lower than that of the general population, with peak oxygen consumption typically reported to range between 50%-70% of predicted values (12).
Quality of life increases substantially after heart transplantation but remains reduced compared with that of the general population (9,14,15).Several factors may contribute to reduced quality of life after heart transplantation, including the trauma associated with the preexisting life-threatening heart failure and the subsequent surgery, as well as comorbidities and adverse effects of lifelong treatment with immunosuppressants.
In the general population, the impact of overweight/obesity on health-related quality of life and physical capacity has been extensively studied.Obesity is associated with reduced functional mobility, fatigue, and depression (16)(17)(18).It is a well-known cause of reduced quality of life in the normal population (19).However, whether weight gain, overweight, and obesity are associated with healthrelated quality of life after heart transplantation remains largely unknown.
In this study we aimed to assess the association between obesity, defined as a body mass index (BMI) ≥30 kg/m 2 , exercise capacity, and health-related quality of life in contemporary heart transplant recipients.

Method The IronIC trial
The randomised, controlled, double-blinded Intravenous Iron supplement for Iron deficiency in Cardiac transplant recipients (IronIC) trial was conducted at Oslo University Hospital, Rikshospitalet, the sole solid organ transplantation center in Norway, and has been reported in detail (20).In summary, 102 maintenance heart transplant recipients with iron deficiency and hemoglobin >100 g/L were randomized 1:1 to ferric derisomaltose or placebo (saline).The primary endpoint, peak oxygen consumption at six months after iron infusion, did not differ significantly between the groups (20).The trial was approved by the Regional Committee for Medical Research Ethics South-East Norway and conducted in compliance with the Declaration of Helsinki.
In this sub study of the Ironic trial, we aimed to assess the association between obesity or overweight and exercise capacity and health-related quality of life in heart transplant recipients.Obesity was defined as a body mass index (BMI) ≥30 kg/m 2 , in line with the cut-off values defined by the World Health Organization (21).

Body composition
We assessed body composition using the InBody 770 bioelectrical impedance analyser.We registered weight and estimated total body water, total fat, skeletal muscle mass, and waist/hip ratio.Percentage body fat and percentage skeletal muscle mass was estimated by dividing fat mass and skeletal muscle mass, respectively, by total body weight and multiplying by 100.

Peak oxygen consumption
We measured peak oxygen consumption on a treadmill with a breath-by-breath gas analyser as described previously (20).The test was continued until subjective fatigue was reached.We used a Borg scale value >18 points or a respiratory exchange ratio >1.05 indicative of an adequate maximal exercise test (22).The 2014 American College of Sports Medicine guidelines was used to determine predicted values (23).Patients who were unable to perform a treadmill test, performed the cardiopulmonary exercise test on an electrically braked bicycle ergometer.

Hand grip strength
We measured hand grip strength using the Kern MAP handheld dynamometer.The patients performed the test three times with their dominant hand.The highest value was recorded.

Health-related quality of life
Health-related quality of life was examined using the SF-36v2 questionnaire, the EuroQol (EQ) 5D-3L and the EQ visualanalogue scale (VAS).The scores were converted into two normbased sum scores: the physical component summary score and the mental component summary score.A minimal clinically important difference was defined as ≥2 for the physical component summary score, and ≥3 for the mental component summary score (24).The EQ-5D-3L questionnaire comprises five questions, each with three response alternatives addressing; mobility, self-care, usual activities, pain/discomfort, and anxiety/ depression (25).We used a Swedish experience based value set to convert the scores into a summery index (26).The EQ VAS instructs the respondent to rate their overall health from 0 to 100 on a vertical visual analogue scale.

Statistical analysis
All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 28 (IBM Corporation).Data are expressed as means ± standard deviation, medians with interquartile range or numbers with percentages as appropriate.Chi-square test, Fisher's exact test, Mann-Whitney U-test, and t-test for independent samples were used as appropriate.A twosided p < 0.05 was considered statistically significant.

The IronIC trial
We enrolled 102 patients in the IronIC trial.Of the 102 participants, 24 patients (24%) were obese.Patient demographics by weight group (≥30 kg/m 2 or <30 kg/m 2 ) are presented in Table 1.Age, sex distribution, and time since transplantation were similar in the two groups.Use of beta blockers and loop diuretics

Body composition
The body fat percentage was higher in the patients with a BMI ≥30 kg/m 2 than in the group with lower BMI; 40 ± 9% vs. 27 ± 9%, p < 0.001 (Figure 1A and Table 1).The percentage of skeletal muscle mass of total body weight was lower in the obese patients compared with those with a BMI <30 kg/m 2 .Furthermore, patients with a BMI ≥30 kg/m 2 had a significantly higher waist-hip ratio.For details, see Table 1.

Peak oxygen consumption
The peak oxygen consumption was 17.3 ± 4.6 ml/kg/min in the patients with BMI ≥30 kg/m 2 vs. 24.7 ± 6.4 ml/kg/min in patients with BMI <30 kg/m 2 , for a between-group difference of 7.4 (95% confidence interval 4.7-10.2) ml/kg/min; p < 0.001 (Figure 1B).The median respiratory exchange ratio was >1.05 and similar in the two groups, suggesting adequate maximal exercise tests in both groups (Table 1).

Hand grip strength
There was no difference in hand grip strength between the patients with obesity and the patients with a BMI <30 kg/m 2 ; (Table 1).

Health-related quality of life
There was a statistically and clinically significant difference in the SF-36 physical component summary score between the two groups.The patients with BMI ≥30 kg/m 2 had a mean physical component summary score of 42.4 ± 10.0 vs. 47.3 ± 9.5 in the patients with BMI <30 kg/m 2 ; p = 0.04 (Figure 1C).On the other hand, there was no difference in the SF-36 mental component summary score between the two groups (Figure 1D).There were no differences in self-reported quality of life, as assessed by the EQ-5D and EQ VAS.For details, see Table 1.

Discussion
Our results suggest that many Norwegian heart transplant recipients have overweight or obesity, resulting in part from obesity prior to transplantation and in part from weight gain after transplantation.Patients with a BMI ≥30 kg/m 2 have substantially lower exercise capacity and lower health-related quality of life in the physical domain.Despite larger absolute muscle mass in the obese patients, hand grip strength and absolute oxygen uptake were not increased relative to those with a BMI <30 kg/m 2 .
Obesity prior to heart transplantation is associated with higher post-transplant mortality and with increased incidence of comorbidities, treated rejections, and cardiac allograft vasculopathy (6)(7)(8).The International Society for Heart Lung Transplantation (ISHLT) and the 2021 The European Society of Cardiology recommend a BMI <35 kg/m 2 prior to listing for heart transplantation (22,27).Excessive weight gain after heart transplantation is associated with an increased risk of cardiac allograft vasculopathy, non-fatal major adverse cardiovascular events, and allograft rejections (4,5).Health-related quality of life and exercise capacity increase after heart transplantation (9, 13-15).There is a positive correlation between health-related quality of life and exercise capacity in heart transplant recipients (10).While the negative effects of obesity on physical capacity and health-related quality of life are well documented in the general population (16)(17)(18)(19), our study suggests that this also holds true for heart transplant recipients.There are already recommendations in place to reduce the risks associated with obesity in heart transplant candidates.However, our results suggest that weight control is important also after heart transplantation.
This study has some important limitations.The number of patients was limited, and the participants of the IronIC trial were required to have iron deficiency as defined in heart failure.However, our previous results suggest that this definition of iron deficiency is too liberal in maintenance heart transplant recipients, and that many of the participants were not truly iron deficient (20).We have no reason to believe that obesity is less prevalent in heart transplant recipients without iron deficiency, or that low iron stores would interact with the relationship between BMI and exercise capacity.Furthermore, our patients were included several years after heart transplantation.This make our data vulnerable for survival bias, and our study is not suitable to address survival.
In summary, obese heart transplant recipients had significantly diminished physical capacity and reduced health-related quality of life.However, we do not know whether normalization of BMI would be associated with improvements in these domains.Clinical trials targeting weight-loss in heart transplant recipients are warranted.